The ongoing COVID-19 pandemic and successful hybrid format dominated much of the discussion at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition, but the lasting impact of the meeting will be the groundbreaking research that was presented. Throughout all diseases, immunotherapy and combination small molecule therapies were common themes, with much discussion centered on measurable residual disease (MRD) as a desirable endpoint in hematologic cancers. Here we will focus on some of the potentially practice-changing studies and most significant data to come from the meeting.
GUEST EDITORS
Alice S. Mims, MD
Jennifer A. Woyach, MD
Dr. Mims is the Acute Leukemia Clinical Research Director and Associate Professor in the Division of Hematology at The Ohio State University Comprehensive Cancer Center – James (OSUCCC – James). Her clinical focus is the treatment of patients with acute and chronic myeloid disease, particularly acute myeloid leukemia. Dr. Woyach is Professor in the Division of Hematology at OSUCCC – James. Her research focuses on targeted therapies for chronic lymphocytic leukemia and strategies to overcome resistance to targeted therapies.
COVID-19 in Hematologic Malignancies
Updated data from the ASH Research Collaborative COVID-19 Registry for Hematology were presented by Lisa K. Hicks, MD, MSc, and colleagues.1 This database is a public-facing volunteer registry that now includes over 1,000 patients. COVID-19 mortality was 17%, and the data confirmed previous findings that age > 60 years, male sex, poor prognosis of the underlying hematologic malignancy, and intensive care unit (ICU) deferral were all associated with higher mortality. In another abstract using this data set, Pinkal Desai, MD, MPH, and colleagues specifically evaluated patients with acute leukemia and myelodysplastic syndrome (MDS).2 In this cohort, COVID-19 mortality was 21%, and poorer outcomes were seen with neutropenia, estimated pre–COVID-19 prognosis of < 6 months, and delayed/forgoing ICU care.
A Surprising Twist for CHIP
At the plenary session, Hind Bouzid, PhD, shared the surprising findings that clonal hematopoiesis of undetermined significance (CHIP) was associated with decreased risk of Alzheimer’s disease.3 CHIP occurs in 10% to 30% of the general population aged ≥ 70 years and is associated with increased risk of cardiovascular disease and a 1% per-year chance of developing a hematologic malignancy. Blood samples were analyzed from 5,730 people enrolled in two precision medicine studies for both CHIP and APOE gene mutations. The APOE e4 allele has shown significant increased risk of Alzheimer’s disease, while the e3 allele reduces risk. A fixed-effects meta-analysis showed a 36% decreased risk for Alzheimer’s disease among CHIP carriers after adjustments for age, sex, and APOE genotype. A small sample of patients with CHIP were found to have the same mutations in 40% to 60% of brain microglial cells, and the hypothesized protective effect is being further explored.
Combination Targeted Agents in CLL
In the field of chronic lymphocytic leukemia (CLL), clinical research over the last few years has been dominated by combinations of Bruton’s tyrosine kinase (BTK) inhibitors with BCL2 inhibitors, which have almost universally demonstrated high rates of undetectable MRD. We saw updates this year on two large studies, the MRD cohort of the phase II CAPTIVATE trial presented by Paolo Ghia, MD, PhD,4 and the phase III GLOW study presented by Tahla Munir, MBBS,5 both investigating combinations of ibrutinib and venetoclax in the front-line setting. The MRD cohort of CAPTIVATE initially treated patients with 1 year of ibrutinib/venetoclax; those patients with detectable MRD then were randomly assigned to ibrutinib or ibrutinib/venetoclax, and those with undetectable MRD randomly assigned to placebo or ibrutinib. At 36 months, there are no observed differences among post–random assignment therapies in either the detectable or undetectable MRD groups, with ≥ 95% progression-free survival in all treatment cohorts. In the GLOW study, patients were randomly assigned to chlorambucil/obinutuzumab vs 1-year ibrutinib/venetoclax. At 30 months, rate of progression-free survival was 80.5% in the ibrutinib/venetoclax arm compared to 35.8% in the chlorambucil/obinutuzumab arm. This registration study may lead to approval of this combination therapy, and ongoing and future research will continue to clarify which patients are best suited to this treatment.
Immunotherapy in Lymphoma
In lymphoma, immunotherapy dominated the clinical trial landscape this year. Three important phase III studies of chimeric antigen receptor (CAR) T-cell vs standard of care therapy for second-line large B-cell lymphoma were presented: ZUMA-7, TRANSFORM, and BELINDA. All of these studies focused on the population of patients progressing within 12 months of initial treatment, with ZUMA-7 including only diffuse large B-cell lymphoma (DLBCL) and the others including aggressive lymphoma of other subtypes. In the plenary session, Frederick L. Lock, MD, presented the results of the ZUMA-7 study of axicabtagene ciloleucel vs standard of care, demonstrating a median event-free survival of 8.3 months with axicabtagene ciloleucel compared with 2.0 months in the standard of care group.6 Similarly, the interim analysis of the TRANSFORM study presented by Manali Kamdar, MD, demonstrated a median event-free survival of 10.1 months vs 2.3 months with standard of care.7 Although still not a home run for these patients, these studies both show potential for earlier CAR T-cell therapy in this high-risk group.
Unfortunately, it is not clear whether this advantage extends to all CAR T-cell products, as is seen with the negative results of the BELINDA trial of tisagenlecleucel vs standard of care in this same patient population, presented by Michael R. Bishop, MD.8 The study authors noted that there may be some unforeseen reasons for the negative results, including higher-risk patients and delays due to bridging chemotherapy in the tisagenlecleucel arm; however, the data at this time suggest that axicabtagene ciloleucel or lisocabtagene maraleucel, but not tisagenlecleucel should become a preferred approach in these patients. Additionally, the ZUMA-12 study presented by Sattva S. Neelapu, MD, showed high rates of response and a 75% 12-month progression-free survival for axicabtagene ciloleucel in the front-line setting, highlighting the potential for CAR T-cell therapy in all lines of treatment.9
In addition to CAR T cells, the potential of immunotherapy with bispecific antibodies was highlighted with a phase II study of the CD3/CD20-bispecific antibody mosunetuzumab in relapsed follicular lymphoma.10 L. Elizabeth Budde, MD, PhD, presented data on this heavily pretreated patient population, showing a response rate of 80% with a complete response rate of 60% and median progression-free survival of 17.9 months. This, coupled with a favorable safety profile and outpatient administration schedule, makes mosunetuzumab a very promising approach for further study.
At the late-breaking abstract session, Hervé Tilly, MD, highlighted outcomes of the POLARIX study of the CD79b antibody-drug conjugate polatuzumab vedotin combined with rituximab/cyclophosphamide/doxorubicin/prednisone.11 In this study, patients with previously untreated DLBCL had a 27% reduction in risk of progression or death with Pola-R-CHP vs R-CHOP, with a 24 month progression-free survival rate of 76.7%. Overall survival is not different at this time, but nonetheless this may herald a change in preferred initial therapy for some patients with DLBCL.
Combination Therapy in MDS and AML
MDS unfortunately continues to have difficulty in advancing past single-agent hypomethylating agents for treatment. Mikkael Sekeres, MD, presented the findings from the PANTHER study, a randomized phase III trial of pevonedistat added to azacitidine vs azacitidine alone in 454 patients with MDS, chronic myelomonocytic leukemia, and low-blast AML.12 The study did not meet the primary endpoint of event-free survival, with the intention-to-treat population showing median event-free survival of 17.7 vs 15.7 months for the combination vs monotherapy arms, respectively. However, both arms showed increasing numbers of hypomethylating agent cycles were associated with better event-free survival and overall survival, reiterating the importance of keeping patients on hypomethylating agent therapy for at least 3 to 6 cycles.
The AGILE study presented by Hartmut Döhner, MD, is a randomized, double-blind, placebo-controlled trial of ivosidenib/azacitidine vs placebo/azacitidine in newly diagnosed IDH1-mutated AML patients who are not candidates for intensive chemotherapy.13 The study halted enrollment as there were significant improvements in event-free survival, median overall survival (24 vs 7.9 months), and complete response rate (47.2% vs 14.9%) with ivosidenib/azacitidine vs placebo/azacitidine. These findings lead to further questions concerning the best upfront choice for this genomic subset of patients, as venetoclax/hypomethylating agent therapy has also shown high response rates.
Advances in Multiple Myeloma
The field of multiple myeloma continues to make headway with incorporating MRD as a clinical trial endpoint. The GMMG-HD7 study is the first phase III study to assess MRD status at the end of induction therapy for newly diagnosed, transplant-eligible patients with multiple myeloma.14 Patients were randomly assigned to the addition of isatuximab, an anti-CD38 antibody, to lenalidomide/bortezomib/dexamethasone (RVd) vs RVd alone as their induction therapy. Hartmut Goldschmidt, MD, reported the rate of MRD negativity was significantly lower in the isatuximab/RVd arm at 50.1% vs 35.6% with RVd alone. However, further clinical trial data are needed to support the ability to use MRD status as a surrogate marker for long-term survival endpoints.
Interim data were reported from two major population studies assessing the role of early screening for monoclonal gammopathy of undetermined significance (MGUS). Habib El-Khoury, MD, presented initial findings from the U.S.-based PROMISE study that performed screening on 7,622 individuals at high risk for developing multiple myeloma.15 The patients underwent screening with both standard MGUS testing as well as higher-sensitivity mass spectrometry assays. Conventional screening found the incidence of MGUS was higher than expected at 6% (vs reported 3%) while the high-sensitivity assay found an even higher rate of 13% for adults age ≥ 50 years. The iStopMM study reported by Sigurdur Y. Kristinsson, MD, PhD, screened more than 80,000 Icelandic adults and detected MGUS in 5% of the overall population.16 Patients that were randomly assigned to intensive follow-up were found to also have a higher incidence of lymphoproliferative disorders. Currently, there remains no recommendations for screening high-risk or general populations for MGUS until longer-term survival data become available and there is more understanding on the impact on patient quality of life.
Conclusion
The 2021 ASH Annual Meeting highlighted continued advancements in hematologic malignancies including screening, immunotherapy, novel small molecular inhibitors, the impact of CHIP, and incorporating MRD into treatment paradigms. However, most importantly, the meeting underscored the resilience of health-care workers, researchers, and, above all, patients with their ongoing efforts to continue to move the field forward despite the major impact of the ongoing COVID-19 pandemic.
DISCLOSURE: Dr. Mims has served on a data safety monitoring board for Daiichi-Sankyo and Jazz Pharmaceuticals; has served as a consultant for Servier Pharmaceuticals and the Leukemia and Lymphoma Society; and has served on an advisory committee for AbbVie, Servier, Bristol Myers Squibb, Astellas, Genentech, and Syndax Pharmaceuticals. Dr. Woyach has served on a data safety monitoring board for Gilead Sciences, Inc; has served as a consultant for AbbVie, ArQule, AstraZeneca Pharmaceuticals, Janssen Biotech, and Pharmacyclics; has served on an advisory committee for AbbVie, Pharmacyclics, Beigene, Loxo Oncology, Newave, and Genentech; and has received research funding from AbbVie, Loxo Oncology, and Schrodinger.
REFERENCES
1. Hicks, LK. Redd RA, Anderson K, et al: 2021 ASH Annual Meeting. Abstract 3040. Presented December 12, 2021.
2. Desai P, Goldberg AD, Anderson KC, et al: 2021 ASH Annual Meeting. Abstract 280. Presented December 11, 2021.
3. Bouzid H, Belk J, Jan M, et al: 2021 ASH Annual Meeting. Abstract 5. Presented December 12, 2021.
4. Ghia P, Allan JN, Siddiqi T, et al: 2021 ASH Annual Meeting. Abstract 68. Presented December 14, 2021.
5. Munir T, Moreno C, Owen C, et al: 2021 ASH Annual Meeting. Abstract 70. Presented December 14, 2021.
6. Locke FL, Miklos DB, Jacobson C, et al: 2021 ASH Annual Meeting. Abstract 2. Presented December 12, 2021.
7. Kamdar M, Solomon SM, Arnason JE, et al: 2021 ASH Annual Meeting. Abstract 91. Presented December 11, 2021.
8. Bishop M, Dickinson M, Purtill D, et al: 2021 ASH Annual Meeting. Abstract LBA-6. Presented December 14, 2021.
9. Neelapu SS, Dickinson M, Munoz J, et al: 2021 ASH Annual Meeting. Abstract 739. Presented December 13, 2021.
10. Budde LE, Sehn LH, Matasar M, et al: 2021 ASH Annual Meeting. Abstract 127. Presented December 11, 2021.
11. Tilly H, Morschhauser F, Sehn L, et al: 2021 ASH Annual Meeting. Abstract 2. Presented December 14, 2021.
12. Sekeres M, Girshova L, Doronin V, et al: 2021 ASH Meeting. Abstract 242. Presented December 11, 2021.
13. Montesinos P, Recher C, Vives S, et al: 2021 ASH Annual Meeting. Abstract 697. Presented December 13, 2021.
14. Goldschmidt H, Mai EK, Nievergall E, et al: 2021 ASH Annual Meeting. Abstract 463. Presented December 12, 2021.
15. El-Khoury H, Alberge J-B, Barr H, et al: 2021 ASH Annual Meeting. Abstract 152. Presented December 11, 2021.
16. Kristinsson SY, Rögnvaldsson S, Thorsteinsdottir S, et al: 2021 ASH Annual Meeting. Abstract 156. Presented December 11, 2021.
